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EP1660034B1 - Fabrication de dispositifs de liberation de medicaments a long terme avec des polymeres a base de polyurethanne - Google Patents

Fabrication de dispositifs de liberation de medicaments a long terme avec des polymeres a base de polyurethanne Download PDF

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Publication number
EP1660034B1
EP1660034B1 EP04769233A EP04769233A EP1660034B1 EP 1660034 B1 EP1660034 B1 EP 1660034B1 EP 04769233 A EP04769233 A EP 04769233A EP 04769233 A EP04769233 A EP 04769233A EP 1660034 B1 EP1660034 B1 EP 1660034B1
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Prior art keywords
drug delivery
delivery device
polyurethane
hollow tube
reservoir
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EP04769233A
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German (de)
English (en)
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EP1660034A2 (fr
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Sheng-Hung Kuo
Petr Kuzma
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Indevus Pharmaceuticals Inc
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Indevus Pharmaceuticals Inc
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Priority to EP14172031.8A priority Critical patent/EP2805709A1/fr
Priority to EP08010973A priority patent/EP1982695A3/fr
Priority to SI200431052T priority patent/SI1660034T1/sl
Priority to PL04769233T priority patent/PL1660034T3/pl
Publication of EP1660034A2 publication Critical patent/EP1660034A2/fr
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Publication of EP1660034B1 publication Critical patent/EP1660034B1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08—Materials for coatings
    • A61L31/10—Macromolecular materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A61P33/06—Antimalarials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T29/00—Metal working
    • Y10T29/49—Method of mechanical manufacture
    • Y10T29/49826—Assembling or joining

Definitions

  • the present invention relates to the field of drug delivery devices and more specifically implantable drug delivery devices made of polyurethane based polymers.
  • polyurethane or polyurethane-containing polymers have been used to fabricate a large number of implantable devices, including pacemaker leads, artificial hearts, heart valves, stent coverings, artificial tendons, arteries and veins. See e.g., www.polymertech.com, www.cardiotech-inc.com, and www.thermedicsinc.com. Also see Hsu et al., Soc. Biomaterials Trans., April 1998 .
  • US 3,993,073 discloses a delivery device for the controlled and continuous administration of a drug to a body site.
  • the device disclosed therein comprises a reservoir containing a dissolved drug surrounded by a shaped wall which is insoluble in body fluid.
  • US 3,948,254 discloses a drug delivery device for the administration of a drug.
  • the drug is contained within a reservoir and the device comprises pores filled with a liquid which is permeable to the passage of the drug.
  • US 5,035,891 A discloses implantable sustained release devices formed from polyurethane tubing.
  • the inventors are not aware of any prior art polyurethane based drug delivery devices which can contain a drug in a solid form and which does not require a liquid medium or carrier for the diffusion of the drug at a zero order rate.
  • a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having:
  • the polyurethane based polymer is selected from the group consisting of: thermoplastic polyurethane, and thermoset polyurethane. Even more preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof.
  • thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof.
  • thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/ or initiators as cross-linking members.
  • the drug delivery device is made of polyurethane which comprises hydrophilic pendant groups.
  • the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof.
  • the drug delivery device may comprise hydrophobic pendant groups.
  • the hydrophobic pendant groups may be selected from alkyl and siloxane groups and mixtures thereof.
  • Another object of the present invention is a process of manufacturing a drug delivery device, said process comprising:
  • the sealing steps are carried out by using pre-fabricated plugs which are inserted on the open ends of the hollow tube with heat or solvent.
  • Yet another object of the present invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, said process comprising:
  • the sealing of an open end is done by inserting a pre-fabricated end plug at the open end of the hollow tube or by using light or heat.
  • Another object of the present invention involves a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S.5,292,515 .
  • suitable means are preferably pharmaceutically acceptable adhesives.
  • Yet another object of the invention is a process of manufacturing drug delivery devices made with thermoset polyurethanes, wherein the sealing of an open end, is done by inserting a pre-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation on interface between the pre-fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently.
  • a drug delivery device for releasing one or more drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects, said drug delivery device having:
  • the polyurethane based polymer comprises a hydrophilic pendant group selected from the group consisting of ionic groups, carboxyl groups, ether groups, hydroxyl groups, and mixtures of any two or more thereof.
  • the polyurethane based polymer is selected from the group comprising: thermoplastic polyurethane, and thermoset polyurethane. More preferably, the thermoplastic polyurethane is made of macrodials, diisocyanates, difunctional chain extenders or mixtures thereof. Also more preferably, the thermoset polyurethane is made of multifunctional polyols, isocyanates, chain extenders or mixtures thereof.
  • thermoset polyurethane comprises a polymer chain and cross-linking members, said thermoset polyurethane contains unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators as cross-linking members.
  • the polyurethane comprises functional groups comprising hydrophilic pendant groups.
  • the hydrophilic pendant groups are selected from ionic, carboxyl, ether, hydroxyl groups and mixtures thereof.
  • the drug delivery device may comprise hydrophobic pendant groups.
  • the hydrophobic pendant groups may be selected from alkyl, siloxane groups and mixtures thereof.
  • thermoplastic polyurethanes made with thermoplastic polyurethanes, said process comprising:
  • the sealing steps are carried out by using pre-fabricated plugs which are inserted on the open ends of the hollow tube with heat or solvent.
  • thermoset polyurethanes made with thermoset polyurethanes
  • thermoset polyurethane formulation The production of the hollow tube and the sealing of an open end are done with an appropriate heat-initiated thermoset polyurethane formulation and initiating and curing the heat-initiated thermoset polyurethane formulation with heat seal the ends, preferably permanently.
  • the sealing of an open end is done by inserting a pre-fabricated end plug at the open end of the hollow tube by suitable means, for example, as described in U.S. 5,292,515 .
  • suitable means are preferably pharmaceutically acceptable adhesives.
  • the sealing of an open end is done by inserting a pre-fabricated end plug at the open end of the hollow tube and by applying an appropriate light-initiated and/ or heat-initiated thermoset polyurethane formulation on interface between the pre-fabricated end plug and the open end and initiating and curing with light and/or heat or any other means to seal the ends, preferably permanently.
  • this invention uses polyurethane based polymers as drug delivery devices for releasing drugs at controlled rates for an extended period of time to produce local or systemic pharmacological effects.
  • the drug delivery device is preferably comprised of a cylindrically shaped reservoir surrounded by polyurethane based polymer through which controls the delivery rate of the drug inside the reservoir.
  • the reservoir is comprised of active ingredients and, optionally, pharmaceutically acceptable carriers. The carriers are formulated to facilitate the diffusion of the active ingredients through the polymer and to ensure the stability of the drugs inside the reservoir.
  • the current invention provides a drug delivery device that can achieve the following objectives: a controlled release rate (zero order release rate) to maximize therapeutic effects and minimize unwanted side effects; an easy way to retrieve the device if it is necessary to end the treatment; an increase in bioavailability with less variation in absorption and no first pass metabolism.
  • a controlled release rate zero order release rate
  • the release rate of the drug is governed by the Fick's Law of Diffusion as applied to a cylindrically shaped reservoir device (cartridge).
  • the permeability coefficient is primarily regulated by the hydrophilicity/hydrophobicity of the polymer, the structure of the polymer, and the interaction of drug and the polymer.
  • the preferably cylindrically shaped device can be manufactured through precision extrusion or precision molding process for thermoplastic polyurethane polymers, and reaction injection molding or spin casting process for thermosetting polyurethane polymers.
  • the cartridge can be made with either one end closed or both ends open.
  • the open end can be plugged with pre-manufactured end plug to ensure a smooth end and a solid seal.
  • the solid actives and carriers can be compressed into pellet form to maximize the loading of the actives.
  • radiopaque material can be incorporated into the delivery device by inserting it into the reservoir or by making it into end plug to be used to seal the cartridge.
  • the cartridges are sealed on both ends with filled reservoir, they are conditioned and primed for an appropriate period of time to ensure a constant delivery rate.
  • the conditioning of the drug delivery devices involves the loading of the actives (drug) into the polyurethane based polymer which surrounds the reservoir.
  • the priming is done to stop the loading of the drug into the polyurethane based polymer and thus prevent loss of the active before the actual use of the implant.
  • the conditions used for the conditioning and priming step depend on the active, the temperature and the medium in which they are carried out. The conditions for the conditioning and priming may be the same in some instances.
  • the conditioning and priming step in the process of the preparation of the drug delivery devices is done to obtain a determined rate of release of a specific drug.
  • the conditioning and priming step of the implant containing a hydrophilic drug is preferably carried out in an aqueous medium, more preferably in a saline solution.
  • the conditioning and priming step of a drug delivery device comprising a hydrophobic drug is usually carried out in a hydrophobic medium such as an oil based medium.
  • the conditioning and priming steps are carried out by controlling three specific factors namely the temperature, the medium and the period of time.
  • a hydrophilic drug would be preferably conditioned and primed in an aqueous solution and more preferably, in a saline solution.
  • Histrelin and Naltrexone implants have been conditioned and primed in saline solution, more specifically, conditioned in saline solution of 0.9 % sodium content and primed in saline solution of 1.8% sodium chloride content.
  • the temperature used to condition and prime the drug delivery device may vary across a wide range of temperatures but, in some instances 37°C, has been preferably used.
  • the time period used for the conditioning and priming of the drug delivery devices may vary from a single day to several weeks depending on the release rate desired for the specific implant or drug.
  • a person skilled in the art will understand the steps of conditioning and priming the implants is to optimize the rate of release of the drug contained within the implant. As such, a shorter time period spent on the conditioning and the priming of a drug delivery device results in a lower rate of release of the drug compared to a similar drug delivery device which has undergone a longer conditioning and priming step.
  • the temperature in the conditioning and priming step will also affect the rate of release in that a lower temperature results in a lower rate of release of the drug contained in the drug delivery device when compared to a similar drug delivery device which has undergone a treatment at a higher temperature.
  • the sodium chloride content of the solution will also determine what type of rate of release will be obtained for the drug delivery device. More specifically, a lower content of sodium chloride would result in a higher rate of release of drug when compared to a drug delivery device which has undergone a conditioning and priming step where the sodium chloride content was higher.
  • conditioning and priming medium be hydrophobic medium, more specifically an oil based medium.
  • the drug (actives) that can be delivered include drugs that can act on the central nervous system, psychic energizers, tranquilizers, anti-convulsants, muscle relaxants, anti-parkinson, analgesic, anti-inflammatory, anesthetic, antispasmodic, muscle contractants, anti-microbials, anti-malarials, hormonal agents, sympathomimetic, cardiovascular, diuretics, anti-parasitic and the like.
  • the current invention focuses on the application of polyurethane based polymers, thermoplastics or thermosets, to the creation of implantable drug devices to deliver biologically active compounds at controlled rates for prolonged period of time.
  • Polyurethane polymers are preferably made into cylindrical hollow tubes with one or two open ends through extrusion, (reaction) injection molding, compression molding, or spin-casting (see e.g. U.S. patents 5,266,325 and 5,292,515 ), depending on the type of polyurethane used.
  • Thermoplastic polyurethane can be processed through extrusion, injection molding, or compression molding.
  • Thermoset polyurethane can be processed through reaction injection molding, compression molding, or spin-casting.
  • the dimensions of the cylindrical hollow tube are very critical and need to be as precise as possible.
  • Polyurethane based polymers are synthesized from multi-functional polyols, isocyanates and chain extenders. The characteristics of each polyurethane can be attributed to its structure.
  • Thermoplastic polyurethanes are made of macrodials, diisocyanates, and difunctional chain extenders (e.g. U.S. patents 4,523,005 and 5,254,662 ). Macrodials make up the soft domains. Diisocyanates and chain extenders make up the hard domains. The hard domains serve as physical crosslinking sites for the polymers. Varying the ratio of these two domains can alter the physical characteristics of the polyurethanes.
  • Thermoset polyurethanes can be made of multifunctional (greater than difunctional) polyols and/or isocyanates and/or chain extenders (e.g. U.S. patents 4,386,039 and 4,131,604 ).
  • Thermoset polyurethanes can also be made by introducing unsaturated bonds in the polymer chains and appropriate crosslinkers and/or initiators to do the chemical crosslinking (e.g. U.S. patent 4,751,133 ). By controlling the amounts of crosslinking sites and how they are distributed, the release rates of the actives can be controlled.
  • hydrophilic pendant groups selected from the group consisting of ionic, carboxyl, ether, and hydroxyl groups are incorporated into the polyols to increase the hydrophilicity of the polymer (e.g. U.S. patents 4,743,673 and 5,354,835 ).
  • hydrophobic pendant groups such as alkyl, siloxane groups are incorporated into the polyols to increase the hydrophobicity of the polymer (e.g. U.S. patent 6,313,254 ).
  • the release rates of the actives can also be controlled by the hydrophilicity/hydrophobicity of the polyurethane polymers.
  • the next step is to determine the best method to fabricate the cylindrically shaped implants.
  • thermoplastic polyurethanes precision extrusion and injection molding are the preferred choices to produce two open-end hollow tubes (see Figure 1 ) with consistent physical dimensions.
  • the reservoir can be loaded freely with appropriate formulations containing actives and carriers or filled with pre-fabricated pellets to maximize the loading of the actives.
  • One open end needs to be sealed first before the loading of the formulation into the hollow tube.
  • two pre-fabricated end plugs are used. The sealing step can be accomplished through the application of heat or solvent or any other means to seal the ends, preferably permanently.
  • thermoset polyurethanes precision reaction injection molding or spin casting is the preferred choice depending on the curing mechanism.
  • Reaction injection molding is used if the curing mechanism is carried out through heat and spin casting is used if the curing mechanism is carried out through light and/or heat.
  • hollow tubes with one open end are made by spin casting.
  • hollow tubes with two open ends are made by reaction injection molding.
  • the reservoir can be loaded in the same way as the thermoplastic polyurethanes.
  • an appropriate heat-initiated thermoset polyurethane formulation is used to fill the open end and this is cured with heat.
  • a pre-fabricated end plug can also be used to seal the open end by applying an appropriate light-initiated and/or heat-initiated thermoset polyurethane formulation on to the interface between the pre-fabricated end plug and the open end and cured it with the light and/or heat or any other means to seal the ends, preferably permanently.
  • the final process involves the conditioning and priming of the implants to achieve the delivery rates required for the actives.
  • the appropriate conditioning and priming media will be chosen. Water based media are preferred for hydrophilic actives and oil based media are preferred for hydrophobic actives.
  • Tecophilic polyurethane polymer tubes are supplied by Thermedics Polymer Products and manufactured through a precision extrusion process.
  • Tecophilic polyurethane is a family of aliphatic polyether-based thermoplastic polyurethane which can be formulated to different equilibrium water content contents of up to 150% of the weight of dry resin. Extrusion grade formulations are designed to provide maximum physical properties of thermoformed tubing or other components.
  • the physical data for the polymers is provided below as made available by Thermedics Polymer Product.
  • Hp-60D-20 is extruded to tubes with thickness of 0.30 mm with inside diameter of 1.75 mm.
  • the tubes are then cut into 25 mm in length.
  • One side of the tube is sealed with heat using a heat sealer.
  • the sealing time is less than 1 minute.
  • Four pellets of histrelin acetate are loaded into the tube. Each pellet weighs approximately 13.5 mg for a total of 54 mg.
  • Each pellet is comprised of a mixture of 98% histrelin and 2% stearic acid.
  • the second end open of the tube is sealed with heat in the same way as for the first end.
  • the loaded implant is then conditioned and primed. The conditioning takes place at room temperature in a 0.9% saline solution for 1 day. Upon completion of the conditioning, the implant undergoes priming.
  • the priming takes place at room temperatures in a 1.8% saline solution for 1 day.
  • Each implant is tested in vitro in a medium selected to mimic the pH found in the human body.
  • the temperature of the selected medium was kept at approximately 37°C during the testing.
  • the release rates are shown on Figure 4 .
  • HP-60D-35 is extruded to tubes with thickness of 0.30 mm with inside diameter of 1.75 mm.
  • the tubes are then cut into 32 mm in length.
  • One side of the tube is sealed with heat using a heat sealer.
  • the sealing time is less than 1 minute.
  • Six pellets of naltrexone are loaded into the tubes and both open sides of the tubes are sealed with heat. Each pellet weighs approximately 15.0 mg for a total of 91 mg.
  • the second end open of the tube is sealed with heat in the same way as for the first end.
  • the loaded implant is then conditioned and primed. The conditioning takes place at room temperature in a 0.9% saline solution for 1 week. Upon completion of the conditioning, the implant undergoes priming.
  • the priming takes place at room temperatures in a 1.8% saline solution for 1 week.
  • Each implant is tested in vitro in a medium selected to mimic the pH found in the human body.
  • the temperature of the selected medium was kept at approximately 37°C during the testing.
  • the release rates are shown on Figure 5 .
  • Figure 7 shows a plot of the release rate of histrelin (LHRH Agonist) versus time.
  • the polymer in this example had a water content of 15%.
  • the polymer used was Tecophilic HP-60-D20 from Thermedics. The data points were taken weekly.
  • Figure 8 shows a plot of the release rate of clonidine versus time.
  • the polymer in this example has a water content of 15%.
  • the polymer used was Tecophilic HP-60-D20 from Thermedics. The data points were taken weekly.

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  • Endocrinology (AREA)

Claims (25)

  1. Dispositif d'apport de médicaments destiné à libérer un ou des médicaments à des débits libérés contrôlés pendant une période de temps prolongée afin de produire des effets pharmacologiques locaux ou systémiques, ledit dispositif d'apport de médicaments ayant :
    i. au moins un ingrédient actif ; et
    ii. un polymère à base de polyuréthane ayant un groupe latéral hydrophile sélectionné dans le groupe consistant en groupes ioniques, groupes carboxyles, groupes éthers, groupes hydroxyles, et mélanges de deux ou plus de ceux-ci, quels qu'ils soient, configuré de façon à fournir un réservoir en forme de cylindre dans lequel est contenue une quantité efficace d'une formulation comprenant cedit au moins un ingrédient actif.
  2. Procédé de fabrication d'un dispositif d'apport de médicaments, ledit procédé comprenant :
    a) former un tube creux réalisé avec un ou des polyuréthanes thermoplastiques et ayant deux extrémités ouvertes par moulage par injection ou par extrusion ;
    b) sceller une extrémité du tube creux afin de fournir un réservoir ;
    c) charger le réservoir avec une formulation souhaitée contenant un ou des ingrédients actifs et, facultativement, des excipients ;
    d) sceller l'autre extrémité ouverte du tube creux ; et
    e) conditionner et amorcer le dispositif d'apport de médicaments résultant afin de parvenir aux débits d'apport souhaités pour ce ou ces ingrédients actifs ;
    dans lequel le scellement des extrémités ouvertes est réalisé en insérant un bouchon d'extrémité préfabriqué au niveau de l'extrémité ouverte du tube creux.
  3. Procédé de fabrication d'un dispositif d'apport de médicaments, ledit procédé comprenant :
    a) former un tube creux par moulage par injection et réaction ou par moulage par centrifugation, ledit tube creux étant moulé avec un ou des polyuréthanes thermodurcis et ayant une extrémité scellée et une extrémité ouverte afin de définir un réservoir ;
    b) durcir le tube creux ;
    c) charger le réservoir avec une formulation souhaitée contenant un ou des ingrédients actifs et, facultativement, des excipients ;
    d) sceller l'extrémité ouverte du tube creux ; et
    e) conditionner et amorcer le dispositif d'apport de médicaments résultant afin de parvenir aux débits d'apport souhaités pour ce ou ces ingrédients actifs ;
    dans lequel le scellement de l'extrémité ouverte est réalisé en insérant un bouchon d'extrémité préfabriqué au niveau de l'extrémité ouverte du tube creux ou en utilisant de la lumière ou de la chaleur.
  4. Le procédé de l'une ou l'autre des revendications 2 et 3 dans lequel ledit dispositif d'apport de médicaments est conditionné et amorcé dans des conditions choisies pour correspondre aux caractéristiques de solubilité dans l'eau de ce ou ces ingrédients actifs.
  5. Le procédé de la revendication 2 dans lequel le polyuréthane thermoplastique comprend un groupe latéral hydrophile et ce ou ces ingrédients actifs sont hydrophiles.
  6. Le procédé de la revendication 2 dans lequel le polyuréthane thermoplastique comprend un groupe latéral hydrophobe et ce ou ces ingrédients actifs sont hydrophobes.
  7. Le procédé de la revendication 4 dans lequel les conditions de conditionnement et d'amorçage incluent l'utilisation d'un milieu aqueux lorsque ce ou ces ingrédients actifs sont hydrophiles.
  8. Le procédé de la revendication 7 dans lequel le milieu aqueux inclut une solution saline.
  9. Le procédé de la revendication 4 dans lequel les conditions de conditionnement et d'amorçage incluent l'utilisation d'un milieu hydrophobe lorsque ce ou ces ingrédients actifs sont hydrophobes.
  10. Le procédé de la revendication 9 dans lequel le milieu hydrophobe inclut un milieu à base d'huile.
  11. Le dispositif d'apport de médicaments de la revendication 1 dans lequel cet au moins un ingrédient actif est sélectionné parmi des médicaments qui peuvent agir sur le système nerveux central, des psycho-analeptiques, des tranquillisants, des anti-convulsants, des relaxants musculaires, des anti-parkinsoniens, des analgésiques, des anti-inflammatoires, des anesthésiques, des antispasmodiques, des contractants musculaires, des antimicrobiens, des antipaludiques, des agents hormonaux, des sympathomimétiques, des agents cardiovasculaires, des diurétiques, et des antiparasitaires.
  12. Le dispositif d'apport de médicaments de la revendication 1 dans lequel cet au moins un ingrédient actif est sélectionné parmi le naltrexone, l'histréline et la clonidine.
  13. Le dispositif d'apport de médicaments de la revendication 1 dans lequel cet au moins un ingrédient actif est de l'acétate d'histréline.
  14. Le dispositif d'apport de médicaments de la revendication 1 dans lequel cet au moins un ingrédient actif est contenu dans une formulation de médicament solide.
  15. Le dispositif d'apport de médicaments de la revendication 14 dans lequel la formulation de médicament solide inclut un excipient acceptable d'un point de vue pharmaceutique.
  16. Le dispositif d'apport de médicaments de la revendication 1 dans lequel le polymère à base de polyuréthane est sélectionné dans le groupe comprenant du polyuréthane thermoplastique et du polyuréthane thermodurci.
  17. Le dispositif d'apport de médicaments de la revendication 16 dans lequel le polyuréthane thermoplastique est composé de macrodiols, de diisocyanates, d'allongeurs de chaînes difonctionnels ou de mélanges de ceux-ci.
  18. Le dispositif d'apport de médicaments de la revendication 16 dans lequel le polyuréthane thermodurci est composé de polyols multifonctionnels, d'isocyanates multifonctionnels, d'allongeurs de chaînes ou de mélanges de ceux-ci.
  19. Le dispositif d'apport de médicaments de la revendication 16 dans lequel le polyuréthane thermodurci comprend une chaîne polymère et des éléments réticulés, le polyuréthane thermodurci comprenant de plus des liaisons insaturées dans les chaînes polymères et des agents de réticulation appropriés et / ou des initiateurs en tant qu'éléments de réticulation.
  20. Le dispositif d'apport de médicaments de la revendication 1 dans lequel la formulation comprend une ou des pastilles préfabriquées.
  21. Le procédé de l'une ou l'autre des revendications 2 et 3 dans lequel la formulation souhaitée comprend une ou des pastilles préfabriquées.
  22. Le dispositif d'apport de médicaments de la revendication 1 dans lequel ledit dispositif d'apport de médicaments est conditionné et amorcé dans des conditions choisies pour correspondre aux caractéristiques de solubilité dans l'eau de cet au moins un ingrédient actif.
  23. Le dispositif d'apport de médicaments de la revendication 1 dans lequel cet au moins un ingrédient actif est hydrophile.
  24. Le dispositif d'apport de médicaments de la revendication 22 dans lequel les conditions de conditionnement et d'amorçage incluent l'utilisation d'un milieu aqueux lorsque cet au moins un ingrédient actif est hydrophile.
  25. Le dispositif d'apport de médicaments de la revendication 24 dans lequel le milieu aqueux inclut une solution saline.
EP04769233A 2003-08-11 2004-08-11 Fabrication de dispositifs de liberation de medicaments a long terme avec des polymeres a base de polyurethanne Expired - Lifetime EP1660034B1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP14172031.8A EP2805709A1 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
EP08010973A EP1982695A3 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
SI200431052T SI1660034T1 (sl) 2003-08-11 2004-08-11 Proizvodnja naprave za podaljĺ ano sproĺ äśanje zdravil s polimeri na bazi poliuretana
PL04769233T PL1660034T3 (pl) 2003-08-11 2004-08-11 Sposób wytwarzania urządzeń do przedłużonego uwalniania leków, wytworzonych z polimerów opartych na poliuretanie

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US49413203P 2003-08-11 2003-08-11
CA2437639A CA2437639C (fr) 2003-08-11 2003-08-18 Dispositifs de distribution de medicaments a long terme dotes de polymeres a base de polyurethane et leur fabrication
PCT/IB2004/002823 WO2005013936A2 (fr) 2003-08-11 2004-08-11 Fabrication de dispositifs de liberation de medicaments a long terme avec des polymeres a base de polyurethanne

Related Child Applications (2)

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EP08010973A Division EP1982695A3 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
EP14172031.8A Division EP2805709A1 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane

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EP1660034A2 EP1660034A2 (fr) 2006-05-31
EP1660034B1 true EP1660034B1 (fr) 2009-01-21

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EP14172031.8A Withdrawn EP2805709A1 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
EP08010973A Ceased EP1982695A3 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
EP04769233A Expired - Lifetime EP1660034B1 (fr) 2003-08-11 2004-08-11 Fabrication de dispositifs de liberation de medicaments a long terme avec des polymeres a base de polyurethanne

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EP14172031.8A Withdrawn EP2805709A1 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane
EP08010973A Ceased EP1982695A3 (fr) 2003-08-11 2004-08-11 Fabrication de dispositif d'administration de médicament à long terme avec du polyuréthane

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EP (3) EP2805709A1 (fr)
JP (4) JP5060128B2 (fr)
CN (2) CN102133174B (fr)
AT (1) ATE421316T1 (fr)
AU (3) AU2004262999B2 (fr)
CA (1) CA2437639C (fr)
DE (1) DE602004019224D1 (fr)
DK (1) DK1660034T3 (fr)
ES (1) ES2320556T3 (fr)
HR (1) HRP20090209T1 (fr)
MX (1) MXPA06001612A (fr)
PL (1) PL1660034T3 (fr)
PT (1) PT1660034E (fr)
SI (1) SI1660034T1 (fr)
WO (1) WO2005013936A2 (fr)

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7858110B2 (en) 2003-08-11 2010-12-28 Endo Pharmaceuticals Solutions, Inc. Long term drug delivery devices with polyurethane based polymers and their manufacture
CA2437639C (fr) * 2003-08-11 2016-07-05 Valera Pharmaceuticals, Inc. Dispositifs de distribution de medicaments a long terme dotes de polymeres a base de polyurethane et leur fabrication
US20090208540A1 (en) * 2003-08-11 2009-08-20 Indevus Pharmaceuticals, Inc. Implantable device for the delivery of naltrexone and methods of use thereof
CA2570960C (fr) * 2004-06-17 2013-10-01 Valera Pharmaceuticals, Inc. Compositions et methodes de traitement de la puberte centrale precoce
NZ561400A (en) * 2005-03-11 2010-02-26 Endo Pharmaceuticals Solutions Controlled release formulations of octreotide
US7759312B2 (en) * 2005-03-11 2010-07-20 Endo Pharmaceuticals Solutions Inc. Delivery of dry formulations of octreotide
US8114055B2 (en) 2005-05-10 2012-02-14 Palyon Medical (Bvi) Limited Implantable pump with infinitely variable resistor
US8211060B2 (en) 2005-05-10 2012-07-03 Palyon Medical (Bvi) Limited Reduced size implantable pump
US8915893B2 (en) 2005-05-10 2014-12-23 Palyon Medical (Bvi) Limited Variable flow infusion pump system
US7637892B2 (en) * 2005-05-10 2009-12-29 Palyon Medical (Bvi) Limited Variable flow infusion pump system
MX2009011641A (es) * 2007-04-27 2010-03-04 Endo Pharmaceuticals Solutions Agentes de liberacion para dispositivo de implante y metodos para utilizar los mismos.
US8303536B2 (en) * 2007-08-30 2012-11-06 Sunstorm Research Corp. Implantable delivery device
US9775882B2 (en) * 2007-09-20 2017-10-03 Medtronic, Inc. Medical devices and methods including polymers having biologically active agents therein
SI2207568T1 (sl) 2007-11-16 2017-11-30 The Rockefeller University Protitelesa specifična za protifibrilno obliko beta-amiloidnega proteina
JP5622725B2 (ja) 2008-06-25 2014-11-12 エンド ファーマスーティカルズ ソリューションズ インコーポレイテッド．Ｅｎｄｏ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ Ｓｏｌｕｔｉｏｎｓｉｎｃ． エキセナチド及び他のポリペプチド類の持続的送達
US7960335B2 (en) * 2008-06-25 2011-06-14 Endo Pharmaceuticals Solutions Inc. Octreotide implant having a release agent and uses thereof
EP2344122A1 (fr) * 2008-09-30 2011-07-20 Endo Pharmaceuticals Solutions Inc. Dispositif implantable permettant d'administrer de l'octréotide et méthodes d'utilisation correspondantes
EP2344125A1 (fr) * 2008-09-30 2011-07-20 Endo Pharmaceuticals Solutions Inc. Dispositif implantable pour l'administration d'histréline et procédés d'utilisation de celui-ci
WO2010039722A1 (fr) * 2008-09-30 2010-04-08 Endo Pharmaceuticals Solutions Inc. Dispositif implantable pour l’administration de rispéridone et procédés d’utilisation de celui-ci
US20110097380A1 (en) * 2009-10-28 2011-04-28 Warsaw Orthopedic, Inc. Clonidine formulations having antimicrobial properties
WO2011139594A2 (fr) 2010-04-27 2011-11-10 Medtronic, Inc. Bourse artificielle pour administration de médicament intra-articulaire
CN103079542A (zh) * 2010-06-30 2013-05-01 赢创德固赛有限公司 具有内芯凸起部的芯鞘型植入装置
US20190263888A1 (en) 2010-10-19 2019-08-29 Op-T Llc Therapeutic peptides and methods for treating autoimmune related disease
KR101723272B1 (ko) 2011-06-21 2017-04-18 비브이더블유 홀딩 에이쥐 보스웰릭산을 포함하는 메디컬 디바이스
BR112014001450A2 (pt) * 2011-07-20 2017-07-18 F Kiser Patrick dispositivos intravaginais para distribuição de droga
US8685418B2 (en) 2011-10-24 2014-04-01 Endo Pharmaceuticals Inc. Cyclohexylamines
CA2853249A1 (fr) 2011-10-24 2013-05-02 Endo Pharmaceuticals Solutions Inc. Compositions de tizanidine implantables et methodes de traitement associees
US8568360B2 (en) 2011-12-28 2013-10-29 Palyon Medical (Bvi) Limited Programmable implantable pump design
SG10201708522SA (en) 2013-03-15 2017-12-28 Taris Biomedical Llc Drug delivery devices with drug-permeable component and methods
AU2014365823B2 (en) 2013-12-16 2019-05-02 Abs Development 1, Inc. P2X3 and/or P2X2/3 compounds and methods
KR102658706B1 (ko) 2015-04-23 2024-04-17 타리스 바이오메디컬 엘엘씨 약물-투과성 성분을 구비한 약물 전달 장치 및 방법
DK3316891T3 (da) 2015-07-01 2019-12-16 Region Nordjylland Aalborg Univ Hospital Behandling af otitis media med retroaurikulær injektion af et antiinflammatorisk lægemiddel
RU2732502C2 (ru) 2016-02-10 2020-09-18 Ратгерс, Де Стейт Юниверсити Оф Нью Джерси Новые моноклональные антитела к LAM и PIM6/LAM для диагностики и лечения инфекций, вызванных Mycobacterium tuberculosis
ITUA20162094A1 (it) * 2016-03-29 2017-09-29 Cid S P A Perfezionamenti negli stent per il rilascio di principi attivi
US10981976B2 (en) 2016-08-31 2021-04-20 University Of Rochester Human monoclonal antibodies to human endogenous retrovirus K envelope (HERV-K) and use thereof
MX2019003710A (es) 2016-09-30 2019-06-24 Asana Biosciences Llc Compuestos y metodos de p2x3 y/o p2x2/3.
ES3031007T3 (en) * 2017-11-10 2025-07-03 Op T Llc Peptide for preventing, modulating and/or reducing cardiovascular disease
CN113164395A (zh) 2018-10-15 2021-07-23 株式会社钟根堂 注射用长效纳屈酮微粒组合物
AU2020226355A1 (en) * 2019-02-19 2021-09-02 Particle Sciences Inc. Compartmentalized drug delivery devices
US11793854B2 (en) 2019-03-21 2023-10-24 Op-T Llc Methods for reducing symptoms of multiple sclerosis using a six-amino acid long peptide that inhibits CD40-CD150 interaction
CA3157003A1 (fr) 2019-10-07 2021-04-15 Oak Crest Institute Of Science Dispositif d'administration de medicament pouvant etre implante par voie orale
AU2020391230A1 (en) 2019-11-27 2022-06-09 Oak Crest Institute Of Science Sustained release drug delivery device
US12048734B2 (en) 2020-04-17 2024-07-30 Op-T Llc Bioactive peptides and methods of use thereof
CN112169138A (zh) * 2020-10-30 2021-01-05 苏州伟康医疗器械有限公司 导尿管的堵头粘结工艺、导尿管
US11820890B2 (en) 2021-04-01 2023-11-21 Stratasys Inc Pulverulent thermoplastic polymer blends
AU2023205140A1 (en) 2022-01-06 2024-08-01 Oak Crest Institute Of Science Subdermal implant for sustained drug delivery
CN114715483B (zh) * 2022-05-04 2023-09-26 展一智能科技(东台)有限公司 下封堵操作机构及包装箱整理机
CN121038778A (zh) 2023-04-19 2025-11-28 橡冠科学研究院 阴道药物递送装置

Family Cites Families (53)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3993073A (en) * 1969-04-01 1976-11-23 Alza Corporation Novel drug delivery device
US3948254A (en) * 1971-11-08 1976-04-06 Alza Corporation Novel drug delivery device
US3975350A (en) * 1972-08-02 1976-08-17 Princeton Polymer Laboratories, Incorporated Hydrophilic or hydrogel carrier systems such as coatings, body implants and other articles
US4136145A (en) * 1974-07-05 1979-01-23 Schering Aktiengesellschaft Medicament carriers in the form of film having active substance incorporated therein
US4207890A (en) * 1977-01-04 1980-06-17 Mcneilab, Inc. Drug-dispensing device and method
US4131604A (en) * 1977-11-23 1978-12-26 Thermo Electron Corporation Polyurethane elastomer for heart assist devices
US4207809A (en) * 1978-03-20 1980-06-17 Restaurant Technology, Inc. Dual reservoir coffee urn
US4386039A (en) * 1980-02-11 1983-05-31 Thermo Electron Corporation Process for forming an optically clear polyurethane lens or cornea
US4523005A (en) * 1981-10-30 1985-06-11 Thermedics, Inc. Extrudable polyurethane for prosthetic devices prepared from a diisocyanate, a polytetramethylene ether polyol, and 1,4-butane diol
US4469671A (en) * 1983-02-22 1984-09-04 Eli Lilly And Company Contraceptive device
US4751133A (en) * 1984-11-13 1988-06-14 Thermedics, Inc. Medical patches and processes for producing same
US4720384A (en) * 1985-05-03 1988-01-19 E. I. Du Pont De Nemours And Company Manufacture of hollow fine tubular drug delivery systems
US4673565A (en) 1985-05-03 1987-06-16 E. I. Du Pont De Nemours And Company Pharmaceutical compositions containing hollow fine tubular drug delivery systems
JPS62223112A (ja) 1986-03-25 1987-10-01 Rooto Seiyaku Kk 歯周病治療剤
US4743673A (en) * 1986-12-19 1988-05-10 Tyndale Plains-Hunter, Ltd. Hydrophilic carboxy polyurethanes
US5035891A (en) * 1987-10-05 1991-07-30 Syntex (U.S.A.) Inc. Controlled release subcutaneous implant
US5207705A (en) * 1988-12-08 1993-05-04 Brigham And Women's Hospital Prosthesis of foam polyurethane and collagen and uses thereof
US5254662A (en) * 1990-09-12 1993-10-19 Polymedia Industries, Inc. Biostable polyurethane products
US5266325A (en) * 1990-09-28 1993-11-30 Hydro Med Science Division Of National Patent Development Corp. Preparation of homogeneous hydrogel copolymers
AU651654B2 (en) * 1992-01-14 1994-07-28 Endo Pharmaceuticals Solutions Inc. Manufacture of water-swellable hydrophilic articles and drug delivery devices
JP2530079B2 (ja) * 1992-02-05 1996-09-04 ナショナル・パテント・ディベロプメント・コーポレーション 水分膨潤性親水性製品及び薬物放出装置の製造
EP0637323B1 (fr) * 1992-04-24 1998-08-19 The Polymer Technology Group, Inc. Copolymeres et membrane non-poreuse, semi-permeable de ceux-ci, et son utilisation pour filtrer des molecules d'une plage de masses moleculaires predeterminee
US5629008A (en) * 1992-06-02 1997-05-13 C.R. Bard, Inc. Method and device for long-term delivery of drugs
US5354835A (en) * 1993-07-23 1994-10-11 Saudi Basic Industries Corporation Desalination process
US5626862A (en) * 1994-08-02 1997-05-06 Massachusetts Institute Of Technology Controlled local delivery of chemotherapeutic agents for treating solid tumors
WO1996024330A1 (fr) * 1995-02-10 1996-08-15 Medtronic, Inc. Procede et dispositif d'administration d'analgesiques
US5789411A (en) * 1995-09-11 1998-08-04 Lance L. Gooberman P. C. Improvements to rapid opioid detoxification
EP1249229A3 (fr) * 1996-02-02 2005-02-02 ALZA Corporation Libération contrôlée d'un principe actif à l'aide d'un dispositif implantable
FR2752380B1 (fr) * 1996-08-14 1998-10-30 Dow Corning Sa Procede de fabrication d'un dispositif a liberation controlee
AUPO251096A0 (en) * 1996-09-23 1996-10-17 Cardiac Crc Nominees Pty Limited Polysiloxane-containing polyurethane elastomeric compositions
US7728049B2 (en) * 1996-10-08 2010-06-01 Zamore Alan M Irradiation conversion of thermoplastic to thermoset polymers
US20010006677A1 (en) * 1996-10-29 2001-07-05 Mcginity James W. Effervescence polymeric film drug delivery system
MY125849A (en) * 1997-07-25 2006-08-30 Alza Corp Osmotic delivery system, osmotic delivery system semipermeable body assembly, and method for controlling delivery rate of beneficial agents from osmotic delivery systems
US5880571A (en) 1997-09-11 1999-03-09 Sundstrand Corporation Method of and system for controlling a variable speed induction motor
JP4215188B2 (ja) * 1997-12-22 2009-01-28 インターシア セラピューティクス，インコーポレイティド 薬剤供給を調節するデバイスのための速度調節膜
PT1736145E (pt) * 1997-12-30 2012-03-16 Intarcia Therapeutics Inc Sistema de entrega de agente benéfico com obturador de membrana
CA2394077A1 (fr) 1999-12-16 2001-06-21 Trident Technologies, Llc Systeme et procede assurant l'apport prolonge d'un agent therapeutique en meme temps que sa dose de mise en charge de recepteur
US7067116B1 (en) * 2000-03-23 2006-06-27 Warner-Lambert Company Llc Fast dissolving orally consumable solid film containing a taste masking agent and pharmaceutically active agent at weight ratio of 1:3 to 3:1
US20020028857A1 (en) * 2000-03-31 2002-03-07 Holy Norman L. Compostable, degradable plastic compositions and articles thereof
AU2001287349B2 (en) * 2000-09-01 2006-03-02 Palmaya Pty Ltd Slow release pharmaceutical preparation and method of administering same
US6887270B2 (en) * 2002-02-08 2005-05-03 Boston Scientific Scimed, Inc. Implantable or insertable medical device resistant to microbial growth and biofilm formation
DE60327626D1 (de) * 2002-05-23 2009-06-25 Active Implants Corp Gelenk- und zahnimplantate
US7858110B2 (en) 2003-08-11 2010-12-28 Endo Pharmaceuticals Solutions, Inc. Long term drug delivery devices with polyurethane based polymers and their manufacture
US20090208540A1 (en) * 2003-08-11 2009-08-20 Indevus Pharmaceuticals, Inc. Implantable device for the delivery of naltrexone and methods of use thereof
CA2437639C (fr) 2003-08-11 2016-07-05 Valera Pharmaceuticals, Inc. Dispositifs de distribution de medicaments a long terme dotes de polymeres a base de polyurethane et leur fabrication
EP1781264B1 (fr) 2004-08-04 2013-07-24 Evonik Corporation Procede de production de systemes d'administration, et systemes d'administration
NZ561400A (en) * 2005-03-11 2010-02-26 Endo Pharmaceuticals Solutions Controlled release formulations of octreotide
US20080004260A1 (en) * 2006-06-29 2008-01-03 Transcept Pharmaceuticals, Inc. Compositions of 5-HT3 antagonists and dopamine D2 antagonists for treatment of dopamine-associated chronic conditions
MX2009005444A (es) * 2006-11-22 2009-06-02 Organon Nv Sistema de suministro para un farmaco hidrofilico no esteroide no ionizado.
AU2007328207A1 (en) 2006-12-05 2008-06-12 Landec Corporation Drug delivery
US7960335B2 (en) 2008-06-25 2011-06-14 Endo Pharmaceuticals Solutions Inc. Octreotide implant having a release agent and uses thereof
WO2010039722A1 (fr) * 2008-09-30 2010-04-08 Endo Pharmaceuticals Solutions Inc. Dispositif implantable pour l’administration de rispéridone et procédés d’utilisation de celui-ci
EP2344122A1 (fr) 2008-09-30 2011-07-20 Endo Pharmaceuticals Solutions Inc. Dispositif implantable permettant d'administrer de l'octréotide et méthodes d'utilisation correspondantes

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JP2014237699A (ja) 2014-12-18
AU2009202942B2 (en) 2011-01-06
WO2005013936A2 (fr) 2005-02-17
CN102133174B (zh) 2016-05-18
ATE421316T1 (de) 2009-02-15
US8357389B2 (en) 2013-01-22
AU2004262999A1 (en) 2005-02-17
PL1660034T3 (pl) 2009-07-31
US8658195B2 (en) 2014-02-25
SI1660034T1 (sl) 2009-08-31
US20110034566A1 (en) 2011-02-10
AU2009202942A1 (en) 2009-08-13
EP1982695A2 (fr) 2008-10-22
HRP20090209T1 (hr) 2009-06-30
AU2004262999B2 (en) 2009-04-23
US20140135684A1 (en) 2014-05-15
JP2011178782A (ja) 2011-09-15
WO2005013936A3 (fr) 2006-04-13
JP2007502139A (ja) 2007-02-08
JP5060128B2 (ja) 2012-10-31
DE602004019224D1 (de) 2009-03-12
CN102133174A (zh) 2011-07-27
CA2437639A1 (fr) 2005-02-11
US20110059147A1 (en) 2011-03-10
EP2805709A1 (fr) 2014-11-26
CA2437639C (fr) 2016-07-05
DK1660034T3 (da) 2009-05-11
US7842303B2 (en) 2010-11-30
CN1863504A (zh) 2006-11-15
JP2013049678A (ja) 2013-03-14
JP5368497B2 (ja) 2013-12-18
US8343528B2 (en) 2013-01-01
US8529936B2 (en) 2013-09-10
AU2010251786B2 (en) 2012-11-29
AU2010251786A1 (en) 2011-01-06
HK1091145A1 (en) 2007-01-12
EP1982695A3 (fr) 2010-05-26
US20130096496A1 (en) 2013-04-18
HK1160378A1 (zh) 2012-08-17
US20050037078A1 (en) 2005-02-17
PT1660034E (pt) 2009-06-24
US20130310740A1 (en) 2013-11-21
CN1863504B (zh) 2011-05-04
MXPA06001612A (es) 2006-04-28
EP1660034A2 (fr) 2006-05-31

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